The Critical Role of Autophagy in the Pathogenesis of Diabetic Osteoporosis: Mechanisms and Therapeutic Measures.

Diabetic osteoporosis (DOP) represents a significant skeletal complication of diabetes mellitus characterized by compromised bone quality and increased fracture risk. Autophagy, a conserved cellular homeostatic mechanism, serves as a key regulator of bone formation and resorption balance. This review comprehensively examines the pivotal role of autophagy in DOP pathogenesis and explores emerging therapeutic strategies targeting autophagic regulation. Under hyperglycemic conditions, dysregulated autophagy occurs through multiple signaling pathways, including ROS-mTOR, PINK1/Parkin-mediated mitophagy, FoxO transcription factors, AGEs-RAGE and TLR4/NF-κB cascades etc. These disturbances manifest distinctly in various cell types: impaired mineralization of osteoblasts, altered bone resorption of osteoclasts, compromised insulin secretion of pancreatic β-cells, diminished osteogenic differentiation of bone marrow mesenchymal stem cells and adipose-derived stem cells. Current therapeutic approaches targeting autophagy dysregulation include pharmacological interventions such as metformin, rapamycin and vitamin D analogs, autophagy enhancers such as resveratrol and AMPK activators, specific inhibitors regulating excessive autophagic activity, Chinese medicinal compounds and exercise regimens. Emerging strategies also include gene therapy, stem cell transplantation and combined therapeutic approaches that precisely modulate the dynamic balance of autophagic flux. Moreover, we underscore the critical importance of maintaining optimal autophagic activity-neither excessive nor insufficient-in bone cells to preserve metabolic homeostasis and prevent osteoporotic progression in DOP patients. Future research directions should focus on elucidating specific mechanisms of action, identifying optimal intervention timing and exploring synergistic therapeutic combinations to effectively manage this challenging metabolic bone disorder.